In the last 10 years the UCSC Genome Browser has become a standard resource in the field. The number of web hits and users continues to increase, more than doubling in the last four years. The browser is also widely featured in scientific papers and presentations. As genomics penetrates ever more deeply into science and medicine, the value of the browser's definitive collection of data sets mapped to reference genome, coordinated, and made interactively accessible, continues to grow. In the next five years we will tackle several key challenges: (1) Update the UCSC gene set to reflect recent dramatic progress in genomics methods with the widespread use of technologies such as next-generation genome sequencing, RNA-seq, and ChlP-seq; these have deepened our view of human genes, both coding and non-coding, including alternative splice variants, regulatory elements, and haplotype variants. (2) Enhance and unify in a common framework our linkages to functional elements of the genome that have been associated with known human variation by projects such as 1000 Genomes and dbSNP, with homologous elements in other species by projects such as Genome 10K, with experimental information by projects such as ENCODE and Roadmap Epigenomics, and with disease phenotypes by projects such as OMIM and COSMIC. The value to research of these linkages and the advanced integration we create increase sharply as they become more comprehensive and more accurate. (3) Continue the fundamental transition to a more distributed database that started with the development of browser data hubs. Broaden our reach with more remote mirror sites and increased training, and increase the security of data uploaded to the browser by users. These developments are essential for the transition from the era of reference genomics to the era of personal genomics, where the data sets are too large, too distributed, and too sensitive to be handled like reference genome data. Since these data still need to map to a reference genome, these innovations will make the browser more relevant than ever in the era of personal genomes. PUBLIC HEALTH RELEVANCE: RELEVAN; At least half of all diseases have a substantial genomic component. This work will help scientists better understand these diseases and develop new treatments.